The objective of the proposed research is to define the association between genetic polymorphisms of two heme biosynthetic pathway enzymes, uroporphyrinogen decarboxylase (UROD) and co- coprophyrinogen oxidative (CPOX), an atypical porphyrinogenic response to mercury (hg), Hg exposure, and Hg toxicity during low-level environmental Hg exposure that could be used to identify persons who are at increased risk of Hg toxicity during low-level environmental Hg exposure. The specific aims of the proposed research are to (1) develop automated sequencing-based and oligonucleotide ligation assays to identify and define polymorphisms in genes that encode UROD and CPOX, (2) use these assays to identify genetic variants of these enzymes within a well- characterized population of Hg-exposed subjects, (3) define the relationship between observed polymorphisms in the human UROD and CPOX genes and the atypical porphyrinogenic response to Hg, (4) define the potential effect modification of UROD and CPOX polymorphisms, as predictors (biomarkers) of Hg-induced changes in kidney and absence and presence of UROD and CPOX polymorphisms, as predictors (biomarkers of Hg-induced changes in kidney and neurobehavioral functions. We will approach these objectives using novel and establish genetic analytical techniques, along with validated neurobehavioral and clinical testing procedures, in an established, well-characterized and highly motivated human population with low-level Hg exposure comparable to that experienced by persons residing near Superfund hazardous waste sites. The finding of a significant relationship between specific polymorphisms in the UROD and/or CPOX genes and the atypical porphyrinogenic response to Hg would represent the first such discovery of a genetic predisposition to an altered biological response to Hg that could be reflected in altered Hg disposition and associated health risks in human subjects. Inasmuch as the atypical porphyrinogenic response to Hg may serve as a biomarker of susceptibility to Hg toxicity, this project directly addresses the Superfund-legislated mandate to develop advanced techniques to detect, assess, and evaluate human health risks associated with hazardous substances exposures.